Grant S G, Karl K A, Kiebler M A, Kandel E R
Center for Genome Research, University of Edinburgh, UK.
Genes Dev. 1995 Aug 1;9(15):1909-21. doi: 10.1101/gad.9.15.1909.
Signaling by tyrosine kinases is required for the induction of synaptic plasticity in the central nervous system. Comparison of fyn, src, yes, and abl nonreceptor tyrosine kinase mutant mice shows a specific requirement for Fyn in the induction of long-term potentiation at CA1 synapses in the hippocampus. To identify components of a Fyn-dependent pathway that may be involved with hippocampus function we examined tyrosine-phosphorylated proteins in kinase mutant mice. We found that nine proteins were hypophosphorylated specifically in fyn mutants. One of the hypophosphorylated proteins was focal adhesion tyrosine kinase (FAK). FAK also showed reduced activity in immunocomplex kinase assays only in fyn mutants. FAK is expressed at very high levels in the brain but in contrast to non-neural cells, FAK was not restricted to focal adhesion contacts. FAK was found in axons, dendrites, and the intermediate filament cytoskeleton of astrocytes. Brain extracts from the mutants also show specific patterns of compensatory changes in the activity of the remaining Src family kinases. Tyrosine phosphorylation is a critical regulator of FAK, and impairments in FAK signal transduction in fyn mutants may contribute to the mutant neural phenotype.
酪氨酸激酶信号传导是中枢神经系统中诱导突触可塑性所必需的。对fyn、src、yes和abl非受体酪氨酸激酶突变小鼠的比较表明，在海马体CA1突触处诱导长时程增强时对Fyn有特定需求。为了鉴定可能与海马体功能有关的Fyn依赖性途径的成分，我们检测了激酶突变小鼠中酪氨酸磷酸化蛋白。我们发现有九种蛋白在fyn突变体中特异性地低磷酸化。其中一种低磷酸化蛋白是粘着斑酪氨酸激酶（FAK）。仅在fyn突变体的免疫复合物激酶分析中，FAK的活性也显示降低。FAK在脑中高水平表达，但与非神经细胞不同，FAK并不局限于粘着斑接触部位。在轴突、树突和星形胶质细胞的中间丝细胞骨架中都发现了FAK。突变体的脑提取物还显示出其余Src家族激酶活性的特定补偿性变化模式。酪氨酸磷酸化是FAK的关键调节因子，fyn突变体中FAK信号转导的损伤可能导致突变体的神经表型。
